The words a father speaks to his children in the privacy of the home are not overheard at the time, but, as in whispering galleries, they will be clearly heard at the end and by posterity. Jean Paul Richter, writer (1763-1825)
Disclosures Psychopharmacology and ASD Evdokia Anagnostou, MD Clinician Scientist, Bloorview Research Institute Associate Professor, Department of Pediatrics, University of Toronto Consulting: Roche Collaborations: SIEMENS Funding: Ontario Brain Institute, CIHR, DoD, HRSA, NCE- NeuroDevNet, Autism Speaks, PSI, ALVA foundation, Brain Canada Unrestricted grant: Sanofi-Aventis Grant support: SynapDx 1 2 Anxiety/ depression Affective lability Sensory-motor dysfunction Socialcommunication Deficits Repetitive behaviors / restricted interests ASD Impulsive aggression GI dysfunction, sleep dysfunction, ADHD like epilepsy Learning Attention Memory 3 4 Before we get started Principles of making a decision about starting medication ATN toolkits: Autism and Medication: Safe and careful Use: A guide for Families of Children with Autism Challenging Behaviors Toolkit Medication Decision aid toolkit http://www.autismspeaks.ca/research-andservices/resources/tool-kits/ What is the target symptom What are the side effects Other questions: feasibility based on frequency of dosing, requirements for blood work Who should know, who should monitor 5 6 1
Common target symptoms What we knowclinical trials in autism Aggression/ irritability, tantrums, self injury Hyperactivity, Inattention Repetitive behaviors Atypical neuroleptics (e.g. risperidone, aripiprazole) Aggression / Irritability Repetitive behaviors +++ +++ +++ Attention / hyperactivity Sleep Anxiety Depression SSRIs, SNRIs (e.g. fluoxetine, sertraline, citalopram) --- Sleep issues Stimulants (e.g. methylphenidate, amphetamines) +++ α and β modulators ++ - +++ (e.g. clonidine, guanfacine) Mood stabilizers (e.g. valproate ) ++(+) melatonin ++ (+) 7 8 Attention / Hyperactivity Clinical Practice Pathways for Evaluation and Medication Choice for Attention-Deficit/Hyperactivity Disorder Symptoms in Autism Spectrum Disorders Methylphenidate Mahajan R, Bernal MP, Panzer R, Whitaker A, Roberts W, Handen B, Hardan A, Anagnostou E, Veenstra-VanderWeele J; Autism Speaks Autism Treatment Network Psychopharmacology Committee. Pediatrics. 2012 Nov;130 Suppl 2:S125-38. doi: 10.1542/peds.2012-0900J. Review. 9 10 11 12 2
Cochrane Database Syst Rev. 2007 Jan 24;(1): Risperidone for autism spectrum disorder. Jesner OS, Aref-Adib M, Coren E. ADHD like symptoms and autism 2 NE Receptor agonists: (e.g. Jaselskis et al., 1992) Clonidine: Open label and one placebo controlled studies Improvement in hyperactivity, irritability, stereotypies, global severity SE: hypotension, bradycardia, sedation Dosing: Clonidine dosage for ADHD in children is 5 micrograms per kilogram of body weight per day orally in four divided doses. Guanfacine: data moderately positive (Handen et al, 2008) Intuniv dosing: 1-4 mg qd 13 14 15 16 Irritability/aggression Atypical Antipsychotics McPheeters ML, Warren Z, Sathe N, Bruzek JL, Krishnaswami S, Jerome RN, Veenstra-Vanderweele J. A systematic review of medical treatments for children with autism spectrum disorders. Pediatrics. 2011 May;127(5):e1312-21. Evidence for effectiveness only in the case of risperidone and aripiprazole 17 18 3
Atypical Antipsychotics Cochrane Database Syst Rev. 2007 Jan 24;(1): Risperidone for autism spectrum disorder. Jesner OS, Aref-Adib M, Coren E. The only drugs with FDA indication for use in children with ASD (risperidone and aripiprazole) 19 20 Adverse events Pharmacogenetics of risperidone (Hoekstra et al 2010) In RUPP trials Increased appetite Fatigue Drowsiness Drooling Weight gain Other EPS, TD Prolongation of QT (very small effect) hyperprolactinemia In a 8 week open label study Carriers of the HTR2C promoter T allele gained an average of 0.043 ± 0.017 body mass indexstandardized z scores (1.84 ± 1.51 kg) versus 0.64 ± 0.35 z (3.23 ± 1.47 kg) for non-t-allele carriers (p < 0.001). Weight gain appeared to be associated with younger age and higher doses of risperidone. 21 22 Aripiprazole for autism spectrum disorders (ASD) Heidi Ching, Tamara Pringsheim Cochrane library, 16 MAY 2012 Forest plot of comparison: Aripiprazole vs. Placebo in Randomised Controlled Trials, outcome: ABC Irritability Subscale Mean Score Changes. Line-item analysis of the Aberrant Behaviour Checklist: results from two studies of aripiprazole in the treatment of irritability associated with autistic disorder. (Aman et al 2010) Statistically significantly greater improvement was seen with aripiprazole versus placebo (p < 0.05) for all arms in both trials on the ABC-Irritability total subscale score and on the following individual ABC-Irritability items: Mood changes quickly, cries/screams inappropriately, stamps feet/bangs objects. Several additional items measuring tantrum-like behaviours improved in the flexibly dosed trial and at least one arm of the fixed-dose trial (p < 0.05). Measures of self-injurious behaviour, demonstrated numerical, but not statistically significant, improvement in both trials. 23 24 4
1 year open label (continuation and novo) (Marcus et al 2011) Atypical Antipsychotics Drug Starting Dose Effective Dose Dosing Frequency Side-effect Consideration Monitoring Considerations Risperidone 0.25-0.5 0.5-3 QDAY-TID Weight gain, EPS/TD Hyperprolactinemia Sedation Olanzapine 2.5-5 5-40 QDAY-TID Weight gain, EPS/TD Hyperprolactinemia 1 Sedation Quetiapine 25-50 75-800 QDAY-TID Weight gain, EPS/TD Hyperprolactinemia 1 Sedation Ziprasidone 20-40 20-160 QDAY-TID Weight neutral?, EPS, QT prolongation Hyperprolactinemia Behavioral activation Aripiprazole 2.5-5 5-15 QDAY-BID Not quite weight neutral EPS/TD Weight, BMI, Fasting glucose and lipid profile AIMS, Prolactin Weight, BMI, Fasting glucose and lipid profile, AIMS Weight, BMI, Fasting glucose & lipid profile, AIMS Weight, BMI, Fasting glucose and lipid profile AIMS, ECG Weight, BMI, Fasting glucose & lipids, AIMS 25 Modified from Posey et al 2007 26 Repetitive behaviors Thoughts about the construct OCD vs repetitive behaviors of autism Distressing vs pleasurable Distressing to whom? Not pediatrics, not ASD 27 28 Citalopram, STAART King et al 2009 Cochrane Database Syst Rev. 2007 Jan 24;(1): Risperidone for autism spectrum disorder. Jesner OS, Aref-Adib M, Coren E. 29 30 5
Sleep BUT Risk to benefit ratio Dev Med Child Neurol. 2011 Sep;53(9):783-92. Melatonin in autism spectrum disorders: a systematic review and metaanalysis. Rossignol DA, Frye RE. 31 32 Sleep Dev Med Child Neurol. 2011 Sep;53(9):783-92. Melatonin in autism spectrum disorders: a systematic review and metaanalysis. Rossignol DA, Frye RE. 33 34 Unmed needs, no data Monitoring guidelines Anxiety (SSRIs, SNRIs, Buspirone) Depression (SSRIs, SSNRIs, Buproprion) 35 36 6
Use CDC calculator to calculate value 1 CAMESA guidelines http://camesaguideline.org Monitoring Safety of Second Generation Antipsychotics (SGA) in Children Patient Name: Gender: DOB (YYYY/M M/DD): SGA Medication: risperidone (Risperdal) Parameter Target Symptoms (e.g. tics, rage, psychosis): Pre-Treatment 1 Month 2 Month 3 Month 6 Month 9 Month 12 Month Baseline General Information: Assessment Date (YYYY/MM/DD): Patient Age at Assessment: Daily Dose of risperidone: mg mg mg mg mg mg mg Physical Examination Maneuvers: Height (cm) 1 Round to nearest 5, 10, 25, Height percentile 50, 75, 90, or 95 %ile Weight (kg) 1 Round to nearest 5, 10, 25, Weight percentile 50, 75, 90, or 95 %ile BMI (kg/m 2 ) 1 BMI percentile 1 Waist Circumference (at level of umbilicus) (cm) 2 >90, or round to nearest 10, Waist Circumference percentile 25, 50, 75, or 90 %ile Systolic Blood Pressure (mm Hg) 3 Provide range (<50, 50-90, Systolic Blood Pressure percentile 90-95, 95-99, or 99) Diastolic Blood Pressure (mm Hg) 3 Provide range (<50, 50-90, Diastolic Blood Pressure percentile 90-95, 95-99, or 99) Neurological Examination: Neurological Exam Normal or Abnormal? Laboratory Evaluations: #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0! Neurological Exam completed? 4 Test Normal Values 5 5 5 5,8 5,7 Fasting Plasma Glucose 6.1 mmol/l 6, 7 6 6 6,8 6, 7 Fasting Insulin 100 pmol/l 7, 8 8 7 Fasting Total Cholesterol < 5.2 mmol/l 7, 8 8 7 Fasting LDL-C < 3.35 mmol/l 7, 8 8 7 Fasting HDL-C 1.05 mmol/l 7, 8 8 7 Fasting Triglycerides < 1.5 mmol/l AST 7 7 7 ALT 7 7 7 9, 10 10 10 Prolactin 11 11 11 11 11 11 11 11 Amylase Other (e.g. A1C, OGTT, etc.); Please List 37 38 Physician Initials: Ameis SH, Corbett-Dick P, Cole L, Correll CU. Decision making and antipsychotic medication treatment for youth with autism spectrum disorders: applying guidelines in the real world. J Clin Psychiatry. 2013 Oct;74(10):1022-4. 39 40 Dosing Metformin (Riomet ) and matching placebo was donated by Ranbaxy Pharmaceuticals Inc. For children from 6-9 years of age: Started at 250 qhs, increased the 250 bid and then 500bid For children from 10-17 years of age Same titration up to week 4, but then up to 850 bid 41 42 7
43 44 Adverse Events Days of gastrointestinal distress Abnormal feces Metformin (n = 28) Placebo (n = 32) Treatment Difference 16-week 16-week Effect 95% CI p 95% CI p 16-week change 95% CI Change Change Size p Total cholesterol (mmol/l) -0.027 (-0.227,0.173) 0.79-0.085 (-0.268,0.097) 0.35 0.058 (-0.212,0.328) 0.123 0.67 LDL (mmol/l) -0.114 (-0.271,0.043) 0.15-0.011 (-0.158,0.137) 0.89-0.104 (-0.318,0.111) 0.278 0.34 HDL (mmol/l) 0.085 (-0.037,0.206) 0.17-0.025 (-0.136,0.085) 0.65 0.110 (-0.053,0.273) 0.357 0.18 Triglycerides (mmol/l) 0.065 (-0.252,0.382) 0.68 0.070 (-0.222,0.361) 0.63-0.005 (-0.418,0.408) 0.006 0.98 Glucose, fasting (mmol/l) -0.170 (-0.371,0.031) 0.10-0.134 (-0.320,0.052) 0.16-0.036 (-0.287,0.215) 0.064 0.78 Insulin, fasting (pmol/l) 13.7 (-72.5,99.9) 0.75 20.5 (-58.6,99.7) 0.61-6.8 (-123.7,110.1) 0.030 0.91 HOMA-IR 0.53 (-2.39,3.44) 0.72 0.59 (-2.07,3.26) 0.66-0.07 (-3.99,3.86) 0.009 0.97 Hgb A1C (mmol/mol) -0.59 (-1.56,0.39) 0.23 0.37 (-0.51,1.25) 0.41-0.95 (-2.26,0.35) 0.403 0.15 ABC Lethargy -2.08 (-4.80,0.63) 0.13-1.06 (-3.64,1.52) 0.41-1.02 (-4.54,2.50) 0.146 0.56 ABC Stereotypy -0.34 (-1.54,0.85) 0.57-1.16 (-2.30,-0.03) 0.044 0.82 (-0.72,2.36) 0.239 0.29 ABC Hyperactivity -1.14 (-3.79,1.50) 0.39-1.60 (-4.10,0.89) 0.20 0.46 (-3.09,4.00) 0.069 0.80 ABC Inappropriate Speech -0.67 (-1.37,0.03) 0.060-0.11 (-0.77,0.55) 0.74-0.56 (-1.50,0.38) 0.305 0.24 45 46 From disability to possibility 47 8
Methylphenidate 10
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Cochrane Database Syst Rev. 2007 Jan 24;(1): Risperidone for autism spectrum disorder. Jesner OS, Aref-Adib M, Coren E. 13
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Cochrane Database Syst Rev. 2007 Jan 24;(1): Risperidone for autism spectrum disorder. Jesner OS, Aref-Adib M, Coren E. 20
Aripiprazole for autism spectrum disorders (ASD) Heidi Ching, Tamara Pringsheim Cochrane library, 16 MAY 2012 Forest plot of comparison: Aripiprazole vs. Placebo in Randomised Controlled Trials, outcome: ABC Irritability Subscale Mean Score Changes. 23
1 year open label (continuation and novo) (Marcus et al 2011) 25
Atypical Antipsychotics Drug Starting Dose Effective Dose Dosing Frequency Side-effect Consideration Monitoring Considerations Risperidone 0.25-0.5 0.5-3 QDAY-TID Weight gain, EPS/TD Hyperprolactinemia Sedation Olanzapine 2.5-5 5-40 QDAY-TID Weight gain, EPS/TD Hyperprolactinemia 1 Sedation Quetiapine 25-50 75-800 QDAY-TID Weight gain, EPS/TD Hyperprolactinemia 1 Sedation Ziprasidone 20-40 20-160 QDAY-TID Weight neutral?, EPS, QT prolongation Hyperprolactinemia Behavioral activation Aripiprazole 2.5-5 5-15 QDAY-BID Not quite weight neutral EPS/TD Weight, BMI, Fasting glucose and lipid profile AIMS, Prolactin Weight, BMI, Fasting glucose and lipid profile, AIMS Weight, BMI, Fasting glucose & lipid profile, AIMS Weight, BMI, Fasting glucose and lipid profile AIMS, ECG Weight, BMI, Fasting glucose & lipids, AIMS Modified from Posey et al 2007 26
Not pediatrics, not ASD 27
Citalopram, STAART King et al 2009 29
Cochrane Database Syst Rev. 2007 Jan 24;(1): Risperidone for autism spectrum disorder. Jesner OS, Aref-Adib M, Coren E. 30
Sleep Dev Med Child Neurol. 2011 Sep;53(9):783-92. Melatonin in autism spectrum disorders: a systematic review and metaanalysis. Rossignol DA, Frye RE. 32
Sleep Dev Med Child Neurol. 2011 Sep;53(9):783-92. Melatonin in autism spectrum disorders: a systematic review and metaanalysis. Rossignol DA, Frye RE. 33
CAMESA guidelines http://camesaguideline.org Monitoring Safety of Second Generation Antipsychotics (SGA) in Children Patient Name: Gender: DOB (YYYY/MM/DD): SGA Medication: risperidone (Risperdal) General Information: Parameter Physical Examination Maneuvers: Height (cm) Height percentile 1 Round to nearest 5, 10, 25, 50, 75, 90, or 95 %ile Weight (kg) Weight percentile 1 Round to nearest 5, 10, 25, 50, 75, 90, or 95 %ile BMI (kg/m 2 ) 1 BMI percentile 1 Use CDC calculator to calculate value 1 Waist Circumference (at level of umbilicus) (cm) Waist Circumference percentile 2 >90, or round to nearest 10, 25, 50, 75, or 90 %ile Systolic Blood Pressure (mm Hg) Systolic Blood Pressure percentile 3 Provide range (<50, 50-90, 90-95, 95-99, or 99) Diastolic Blood Pressure (mm Hg) Diastolic Blood Pressure percentile 3 Provide range (<50, 50-90, 90-95, 95-99, or 99) Neurological Examination: Neurological Exam completed? 4 Neurological Exam Normal or Abnormal? Laboratory Evaluations: Test Fasting Plasma Glucose 5 Fasting Insulin 6, 7 Fasting Total Cholesterol 7, 8 Fasting LDL-C 7, 8 Fasting HDL-C 7, 8 Fasting Triglycerides 7, 8 Normal Values 6.1 mmol/l 100 pmol/l < 5.2 mmol/l < 3.35 mmol/l 1.05 mmol/l < 1.5 mmol/l Target Symptoms (e.g. tics, rage, psychosis): mg mg mg mg mg mg mg 5 5 5,8 5,7 6 6 6,8 6, 7 8 7 8 7 8 7 8 7 AST 7 7 7 ALT 7 7 7 9, 10 Prolactin 10 10 11 Amylase 11 11 11 11 11 11 11 Other (e.g. A1C, OGTT, etc.); Please List Assessment Date (YYYY/MM/DD): Patient Age at Assessment: Daily Dose of risperidone: Physician Initials: Pre-Treatment Baseline #DIV/0! 1 Month #DIV/0! 2 Month #DIV/0! 3 Month #DIV/0! 6 Month #DIV/0! 9 Month 12 Month #DIV/0! #DIV/0! 37
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Metformin (n = 28) Placebo (n = 32) Treatment Difference 16-week Change 95% CI p 16-week Change 95% CI p 16-week change 95% CI Effect Size p Total cholesterol (mmol/l) -0.027 (-0.227,0.173) 0.79-0.085 (-0.268,0.097) 0.35 0.058 (-0.212,0.328) 0.123 0.67 LDL (mmol/l) -0.114 (-0.271,0.043) 0.15-0.011 (-0.158,0.137) 0.89-0.104 (-0.318,0.111) 0.278 0.34 HDL (mmol/l) 0.085 (-0.037,0.206) 0.17-0.025 (-0.136,0.085) 0.65 0.110 (-0.053,0.273) 0.357 0.18 Triglycerides (mmol/l) 0.065 (-0.252,0.382) 0.68 0.070 (-0.222,0.361) 0.63-0.005 (-0.418,0.408) 0.006 0.98 Glucose, fasting (mmol/l) -0.170 (-0.371,0.031) 0.10-0.134 (-0.320,0.052) 0.16-0.036 (-0.287,0.215) 0.064 0.78 Insulin, fasting (pmol/l) 13.7 (-72.5,99.9) 0.75 20.5 (-58.6,99.7) 0.61-6.8 (-123.7,110.1) 0.030 0.91 HOMA-IR 0.53 (-2.39,3.44) 0.72 0.59 (-2.07,3.26) 0.66-0.07 (-3.99,3.86) 0.009 0.97 Hgb A1C (mmol/mol) -0.59 (-1.56,0.39) 0.23 0.37 (-0.51,1.25) 0.41-0.95 (-2.26,0.35) 0.403 0.15 ABC Lethargy -2.08 (-4.80,0.63) 0.13-1.06 (-3.64,1.52) 0.41-1.02 (-4.54,2.50) 0.146 0.56 ABC Stereotypy -0.34 (-1.54,0.85) 0.57-1.16 (-2.30,-0.03) 0.044 0.82 (-0.72,2.36) 0.239 0.29 ABC Hyperactivity -1.14 (-3.79,1.50) 0.39-1.60 (-4.10,0.89) 0.20 0.46 (-3.09,4.00) 0.069 0.80 ABC Inappropriate Speech -0.67 (-1.37,0.03) 0.060-0.11 (-0.77,0.55) 0.74-0.56 (-1.50,0.38) 0.305 0.24 46